"We
have received disturbing information on the WHO alert system that the
U.S. two people the virus H3N2: a seven-month child in Illinois and
46-year-old man in Pennsylvania, "- told Interfax Rospotrebnadzor head
Gennady Onishchenko.

The WHO wants to be ready to
make recommendations and issue guidance to countries if the need arises
— though Fukuda stressed at this point it is far from certain there
will be that need.

"We're very aware that we
don't want to over-play or under-play. We're trying to get that right,"
says Fukuda, a leading influenza expert.

"(We're) trying to make sure
that we're ready to move quickly, if we have to move quickly, but also
trying not to raise alarm bells."

The desire to be prepared
without raising alarm is a legacy of the 2009 H1N1 pandemic. The WHO
was heavily criticized in Europe for declaring that event a pandemic
when the outbreak turned out to be far milder than originally feared.

But what exactly the agency
— and the world — might need to prepare for now is very unclear. With
the public relations problems of the 2009 outbreak fresh in the minds
of health officials, no one is using the "p" word these days.

The alert issued in November, 2010 cited two trH3N2 isolates
(A/Wisconsin/12/2010 and A/Pennsylvania/14/2010), but WHO
and the CDC were probably aware of a third case
(A/Pennsylvania/40/2010) who developed symptoms less than a week prior
to the Wisconsin case (cited as an Illinois cases in the alert).

If the WHO and CDC didn’t know about the second Pennsylvania case when
the alert was issued, within days they knew of that case, as well as a
case from Minnesota (A/Minnesota/11/2010) and symptomatic
contacts. When the CDC released the sequences from these cases,
there was clear cause for concern, as seen in slide 7 from the CDC
(Nancy Cox) presentation in February, 2011 (at the FDA vaccine
advisory committee meeting).

The H3 sequences from cases in Wisconsin, Pennsylvania, and Minnesota
were clustering, indicating the H3 for all three cases were remarkably
similar and distinct from trH3N2 swine isolates. Moreover, the
sequences from the Wisconsin case and the Pennsylvania case that was
not mentioned in the alert, were virtually identical, creating striking
parallels between the trH3N2 data and the initial cases in southern
California at the start of the H1N1 pandemic in 2009.

However, the absence of the sequences from the second case allowed the
CDC to offer assurances that there was no human transmission because of
sequence differences between the two cases in the alert, which were
isolated 6 weeks apart. The announcement of the second case in
Pennsylvania was delayed until February 5, because the case was
initially classified as seasonal H3N2, but sequence data showed that
the case was clearly trH3N2. That sequence was used in slides 7
and 8 in the CDC February 25, 2011 presentation, but the sequence was
not released until Sunday, April 17, 2011 at GISAID without comment.
As seen in slides 7 and 8, the PA/40/2010 sequence was virtually
identical to WI/12/2010 and this identity extended to all 8 gene
segments. Moreover the two cases developed symptoms within a week
of each other, even though they were not epidemiologically
linked. Thus, the only significant difference between the trH3N2
matches in 2010 and the trH1N1 matches in 2009 was the claim of “swine
exposure” for the trH3N2 cases.

However, this “exposure” was listed
in the CDC slide as a “visit to a local animal fair”. Since
the Wisconsin case was only seven months old at the time, the extent of
“contact” was likely limited, and no trH3N2 was reported at any of the
swine at the fair. Similarly, the Pennsylvania case (3F) was only
3 years of age, and swine contact at the fair was also likely limited,
and no trH3N2 matching the human cases has been reported from either
state. Similarly, the other case from Pennsylvania (PA/14/2010)
had no reported exposure to swine, although he lived in a rural area
(and closely related sequences to this case were subsequently
identified in Pennsylvania swine).

Thus, the red flag raised over a year ago in the WHO pager alert
signaled the start of a series of events which left little doubt that
the trH3N2 had begun in 2010, and gained significant speed in
2011. In week 21 of 2011 trH3N2 was lab confirmed (serologically)
in the daughter of the Minnesota case and her lack of swine exposure
led to the CDC concession that the case represented limited human to
human transmission.

This concession was made again for the first 2011 trH3N2 case (A/Indiana/08/2011),
who also had no swine contact. However, the caretaker of the
patient had swine exposure, so the case was said to have “indirect
swine exposure” even though the caretaker and swine were asymptomatic
and not trH3N2 was identified in either case.

Similarly, the first 2011 case from Pennsylvania (A/Pennsylvania/09/2010)
also visited an agricultural fair (Washington county) but no
symptomatic swine was identified at the fair, which included the market
hogs exhibited by the second Pennsylvania case. The third case
also visited the fair and a friend who exhibited swine, but there was
no evidence that any of the three cases were infected by trH3N2 in
swine at the fair, and the sequences from the 2nd and 3rd Pennsylvania
case (A/Pennsylvania/10/2011
and A/Pennsylvania/11/2011)
were virtually identical to the Indiana case.

Thus, the matches between cases that were not epidemiologically linked
as seen in late 2010, was repeated in the initial cases in 2011,
although this sequence had evolved from the 2010 sequences by acquiring
an NA gene matching the other Pennsylvania case (PA/14/2010) and an M
gene segment from 2011.

This constellation and lineage has now been found in all
2011 human cases, including the Iowa
cluster, which had no swine contact and involved three confirmed
cases and two symptomatic family members of the index case.

Thus, the “swine exposure’ link, which generated the more advanced
testing at the CDC required to confirm trH3N2, was absent from the Iowa
cluster, leaving little doubt that the novel trH3N2 was spreading in
humans and was orders of magnitude higher than the ten confirmed cases
from four states (Indiana, Pennsylvania, Maine, Iowa) as well as one
novel trH3N2 swine isolate from New York, A/swine/NY/A01104005/2011.

Consequently, WHO is planning for the trH3N2 pandemic, without using
the “P” word.